The GBA1 NM_000157.4:c.1448T>C (NP_000148.2:p.(Leu483Pro)) missense variant has not previously been reported in somatic cancers (COSMIC). Experimental evidence: L444P-associated cells showed deficient glucocerebrosidase activity and absent protein, but complex-allele confounding prevents strong PS3 application. Based on available guidelines, this variant is considered to be Pathogenic.
Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
Pathogenic.A pathogenic classification under the recorded framework.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.GBA1 encodes glucocerebrosidase, a lysosomal enzyme that breaks down glucosylceramide, an intermediate in glycolipid metabolism. Loss of this enzyme's activity causes Gaucher disease, a lysosomal storage disorder characterized by the accumulation of glucocerebrosides in cells. No direct role in cancer has been established for this gene.
The recorded framework is Generic ACMG/AMP 2015 with ClinGen SVI recommendations. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
Met: the exact Leu-to-Pro substitution is an established Gaucher disease mutation in multiple reports, with SpliceAI maximum delta 0.002 indicating no significant splice impact.
Met at supporting strength: L444P-associated cells showed deficient glucocerebrosidase activity and absent protein, but complex-allele confounding prevents strong PS3 application.
Met: p.L444P occurred in 12/144 cases versus 0/100 controls, with continuity-corrected OR 18.96 (95% CI 1.11-324.11), exceeding the >5.0 threshold and excluding 1.
Met: MSM61 carried L444P and 5958T on separate alleles, providing phase-resolved evidence of the queried variant in trans with another disease-associated GBA1 variant.
Met, moderate: missense REVEL 0.858 exceeds the PP3 moderate threshold of >=0.773.
Met: the reported complex allele placed L444P with A456P and V460V in cis in an affected fetus with severe type 2 Gaucher disease.
Pathogenic: PS1 strong plus PS4 strong satisfy the generic ACMG/AMP rule, with additional PM3 and PP3 moderate and PS3 supporting evidence.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 159 / 1,612,982 alleles. Recorded AF 9.85752e-05. Recorded homozygote count 0.
This variant is present in gnomAD v2.1 (AF= 0.00122607; MAF= 0.12261%, 345/281386 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.0024505; MAF= 0.24505%, 25/10202 alleles, homozygotes = 0); grpmax FAF= 0.00119554.
Not available in gnomAD-Canada v1.0.
Recorded REVEL score: 0.858. Refer to the recorded PP3/BP4 rationale for interpretation.
41 Pathogenic · 1 risk factor · 1 pathogenic · 1 Likely pathogenic · 1 Likely Pathogenic. ClinVar API review status: criteria provided, conflicting classifications.
No standalone functional evidence summary is recorded in evidence_summary.functional.
This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under Generic ACMG/AMP 2015 with ClinGen SVI recommendations, with the data and sources behind each one.
28 criteria with recorded statuses: 6 met · 8 not met · 10 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Under generic ACMG/AMP rules because the listed GBA1 VCEP has no released criteria, PS1 is met at strong strength for the established same amino-acid change Leu483Pro/L444P; PM1, PM5, and PP2 remain not assessed for missing criterion-specific evidence, while BP1 is not met because the supplied literature documents multiple disease-associated GBA1 missense alleles.
Functional evidence supports a damaging effect for p.Leu483Pro/L444P, but complex-allele confounding and incomplete assay characterization limit PS3 to supporting strength; no BS3 evidence is available.
PS4 is met because a variant-specific familial Parkinson disease case-control comparison reports 12/144 cases versus 0/100 controls; the continuity-corrected OR is 18.96 with a 95% CI of 1.11-324.11, satisfying OR >5.0 with a confidence interval excluding 1.0.
PP4 is not assessed because patient-level phenotype and family-history specificity are insufficient.
PP5 and BP6 are not met because the exact-variant ClinVar record has no expert-panel classification, and BP5 is not assessed because no alternate molecular basis is documented.
No criteria match.
NM_000157.4:c.1448T>C produces NP_000148.2:p.(Leu483Pro), also reported as mature-protein p.L444P because of the 39-residue numbering offset. Multiple disease-focused publications identify p.L444P/Leu-444-to-Pro as an established Gaucher disease mutation, including affected individuals and families, establishing the same amino-acid change as pathogenic independently of nucleotide representation. The evidence is protein-level and SpliceAI predicts no significant splice impact (maximum delta 0.002), so the PS1 splicing caveat does not preclude application.
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. ... Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
PS3 is met at supporting strength. The queried variant NM_000157.4:c.1448T>C (p.Leu483Pro) is the legacy GBA1 L444P variant. A case report of a fetus with a complex allele containing L444P, A456P, and V460V found no detectable glucocerebrosidase activity and no detectable glucocerebrosidase cross-reactive material despite RNA being present (PMID:8929950); because the allele contains additional variants, the result cannot be attributed exclusively to L444P. An older expression study identified the same Leu-444-to-Pro substitution and found normal transcript expression but too little mutant protein for complete enzymatic characterization, with rapid protein destruction inferred (PMID:1972019). A separate patient-cell study reported markedly reduced beta-glucosidase activity in affected cell lines carrying the variant, but did not perform a variant-specific functional assay (PMID:1899336). These concordant loss-of-function observations support a damaging effect, but the complex allele, limited assay quantitation, and lack of a validated/reproducible clinical-laboratory assay prevent strong-level application.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. ... Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.
PS4 is met under the ACMG/AMP case-control definition. PMID:24126159 reports the exact variant as mature-protein p.L444P, corresponding to NM_000157.4:c.1448T>C / p.(Leu483Pro), in 12 of 144 familial Parkinson disease index patients (8.3%) and 0 of 100 unrelated controls; the paper reports p=0.002. I calculated the odds ratio from these counts using a Haldane-Anscombe 0.5 continuity correction for the zero control cell: OR=18.96, 95% CI 1.11-324.11. The governing threshold is >5.0 and the confidence interval excludes 1.0: 18.96 > 5.0? yes; 1.11-324.11 includes 1.0? no. The literature_pass packet's ai_classified_papers contains no paper classified as PS4, but the full-text extraction for PMID:24126159 independently verifies the variant-specific case-control counts.
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0.
PM3 is met for the recessive Gaucher disease context. PMID:1899336 reports the queried L444P variant (equivalent to NM_000157.4:c.1448T>C, p.Leu483Pro) in patient MSM61 together with 5958T, explicitly stating that the two variants were on separate alleles. This is a phase-resolved observation of the queried variant in trans with another disease-associated GBA1 variant in an affected patient. No quantitative generic ClinGen SVI strength threshold for PM3 was supplied, so no strength sublevel is assigned.
For recessive disorders, detected in trans with a pathogenic variant
The variant is a missense substitution, NM_000157.4:c.1448T>C (p.Leu483Pro), so the applicable generic PP3/BP4 path is REVEL only; SpliceAI is not used for a missense variant, and BayesDel has no generic ACMG-strength calibration. REVEL is 0.858, meeting the supplied PP3 moderate threshold of >=0.773 but not the strong threshold of >=0.932. Therefore PP3 is met at moderate strength, based on the ClinGen SVI REVEL calibration of Pejaver et al. 2022 (PMID:36413997).
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
BP2 is met through the cis pathway. PMID:8929950 reports that the queried L444P variant (equivalent to NM_000157.4:c.1448T>C, p.Leu483Pro) was part of a known complex allele that also included A456P and V460V, establishing cis occurrence with another variant in the same allele. The report concerns an affected fetus with severe type 2 Gaucher disease and documents the complex allele by mutation analysis. No quantitative generic ClinGen SVI strength threshold for BP2 was supplied, so no strength sublevel is assigned.
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
PM2 is not met under the supplied generic SVI threshold. The variant is present in both population datasets: gnomAD v2.1 grpmax FAF=0.00119554 and gnomAD v4.1 grpmax FAF=0.00019859. Both exceed the generic PM2 supporting cutoff of <=0.0001, so the allele is neither absent nor sufficiently rare for PM2. No GBA1-specific VCEP population rule is available, so the default all-comers gnomAD entries govern.
PM2: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. ... PM2 (supporting): <= 0.0001 — SVI recommendation to downgrade PM2 to Supporting (ClinGen SVI 2020) (PMID:25741868)
PP5 is not met. The exact-variant ClinVar record has no expert-panel submission; its Pathogenic and Likely pathogenic assertions are from ordinary laboratory or other non-expert submissions, and the aggregate record is not an expert-panel classification. Therefore it does not satisfy the required exact-variant expert-panel condition for PP5.
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
BA1 is not met. The governing generic stand-alone threshold is allele frequency >=0.05. The highest qualifying filtering allele-frequency measure is the gnomAD v2.1 grpmax FAF of 0.00119554 (0.119554%), based on 345/281386 total alleles; gnomAD v4.1 grpmax FAF is lower at 0.00019859 (0.019859%). Both are far below 0.05. The higher gnomAD v2.1 Ashkenazi Jewish point estimate of 0.0024505 is not used because the required measure is grpmax FAF rather than a popmax point estimate. The variant also has a documented pathogenic ClinVar consensus, but its frequency is far below BA1 and therefore does not create the high-frequency/pathogenicity conflict that would require withholding BA1 on that basis.
BA1: Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. ... BA1 (stand-alone): >= 0.05 — ACMG/AMP 2015 stand-alone benign allele frequency (PMID:25741868)
BS1 is not met on the available population evidence. The governing rule is that allele frequency must be greater than expected for the disorder; the supplied 0.01 value is only a generic default, not an automatic disease-specific conclusion. The required filtering allele frequencies are 0.00119554 in gnomAD v2.1 and 0.00019859 in gnomAD v4.1, both below 0.01. GBA1-associated Parkinson disease has reduced and late-onset penetrance, while Gaucher disease is recessive, so a disorder-specific maximum-credible-frequency calculation would require explicit prevalence, penetrance, and allelic-heterogeneity inputs; none is available here. No observed frequency exceeds the generic default or establishes BS1 under a validated GBA1-specific threshold.
BS1: Allele frequency is greater than expected for disorder. ... BS1 (strong): >= 0.01 — Generic SVI default; per-gene derivation preferred (Whiffin et al. 2017) (PMID:28518168)
BS2 is not met. For recessive GBA1-associated Gaucher disease, the qualifying observation would be a healthy adult homozygous for the variant with full penetrance expected at an early age; gnomAD v2.1 reports zero homozygotes among 281386 alleles and gnomAD v4.1 reports zero among 1612982 alleles. For heterozygous GBA1-associated Parkinson disease, the early-onset/full-penetrance requirement is not satisfied because this is a late-onset, reduced-penetrance risk context. No qualifying healthy-adult observation is documented in the supplied evidence.
Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.
BP1 is applicable because the variant is missense, but the supplied GBA1 literature describes multiple disease-associated missense alleles, including Leu444Pro/L483P, and does not support a gene in which disease is caused primarily by truncating variants. The available evidence therefore contradicts the BP1 gene-level premise.
Missense variant in a gene for which primarily truncating variants are known to cause disease.
The variant is a missense substitution, so REVEL is the sole applicable generic BP4 path; SpliceAI is not used for a missense variant, and BayesDel has no generic ACMG-strength calibration. REVEL is 0.858, which is above the supplied BP4 supporting threshold of <=0.29 and therefore is not evidence for a benign computational effect. The result is not_met rather than not_applicable: missense variants are within BP4 scope, but this applicable REVEL result does not meet BP4.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
BP6 is not met. The exact-variant ClinVar record contains no expert-panel submission and no exact-variant expert-panel Benign or Likely benign classification. Ordinary submissions, aggregate labels, and non-expert assertions cannot trigger BP6.
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
The available case evidence does not document a qualifying de novo event in an affected proband. A ClinVar submission records origin as de novo, but its significance is not provided, no condition is specified, and there is no documentation that both maternity and paternity were confirmed. Therefore PS2 cannot be assessed from this record.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
The GBA1 VCEP is listed without released criteria, and vcep_materials.json contains no authoritative domain table for GBA1. The available evidence reports no statistically significant hotspot for this variant and provides no validated GBA1 critical-domain or benign-variation dataset sufficient to establish the generic PM1 requirement. Therefore PM1 cannot be assessed from the supplied evidence.
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
The supplied PM5 candidate collection contains no same-residue comparator variants and no evidence establishing a different pathogenic missense substitution at residue 483. The literature reviewed for the exact Leu483Pro/L444P variant does not identify a distinct missense change at that residue. A reliable same-residue comparator search or documented comparator evidence is therefore required before PM5 can be assessed.
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. ... Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
The available evidence does not provide a documented affected proband with an assumed de novo variant and a defined parental-testing context. Although a ClinVar submission labels origin as de novo, its significance is not provided, no condition is specified, and no clinical or parental details support treating that label as a PM6 observation. Therefore PM6 cannot be assessed.
Assumed de novo, but without confirmation of paternity and maternity.
PMID:24126159 reports p.L444P, equivalent to p.(Leu483Pro), in two familial Parkinson disease families in which affected siblings carried the same mutation, including Family 28. However, the report does not provide sufficient family-level genotype/phenotype detail to establish the required qualifying segregation for this case, and the study characterizes GBA as a Parkinson disease risk factor rather than demonstrating a definitively disease-causing role for the familial Parkinson disease phenotype. PMID:8929950 describes two affected conceptuses with a complex allele but does not establish segregation. PP1 is therefore not assessed.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. ... Note: May be used as stronger evidence with increasing segregation data.
The supplied evidence documents the queried allele and several pathogenic GBA1 missense alleles, but it does not provide a gene-wide benign-missense rate or a sufficiently comprehensive gene-level analysis showing that missense variants are a common disease mechanism under the generic PP2 definition. The criterion therefore cannot be assessed without those gene-level data.
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
The PP4 rule requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology. The available case evidence identifies the GBA1 variant but does not provide a sufficiently specific phenotype or family-history assessment for the patient being interpreted, so PP4 cannot be adjudicated.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
No well-established functional study in the available evidence demonstrates that NM_000157.4:c.1448T>C (p.Leu483Pro) has no damaging effect on GBA1 protein function or splicing. The available studies instead report absent or markedly reduced glucocerebrosidase activity/protein, or are inconclusive because the variant was studied in a complex allele or yielded insufficient mutant protein. Therefore BS3 cannot be assessed.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
The available evidence contains no documented affected relatives who lack the variant, no family-level non-segregation analysis, and no validated phenocopy assessment. The presence of unrelated affected cases or population controls does not establish lack of segregation in an affected family. Therefore BS4 cannot be assessed.
Lack of segregation in affected members of a family. ... Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals.
BP5 cannot be assessed from the available evidence. No case-level evidence was provided showing this variant in a patient with an alternate molecular basis for the disease, and no governing BP5-specific alternate-basis observation is documented for this case.
Variant found in a case with an alternate molecular basis for disease.
PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_000157.4:c.1448T>C in GBA1 is a missense substitution predicted to produce NP_000148.2:p.(Leu483Pro). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PVS1 for GBA1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_null_variant_class
PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_000157.4:c.1448T>C in GBA1 is a missense substitution predicted to produce NP_000148.2:p.(Leu483Pro). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM4 for GBA1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_000157.4:c.1448T>C in GBA1 is a missense substitution predicted to produce NP_000148.2:p.(Leu483Pro). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP3 for GBA1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_repeat_region_indel
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_000157.4:c.1448T>C in GBA1 is a missense substitution predicted to produce NP_000148.2:p.(Leu483Pro). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for GBA1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
Every interpreted variant in GBA1, mapped onto the exon structure of NM_000157.4. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| Middle Eastern2 / 6,054 | 0.00033 |
| African/African American22 / 74,930 | 0.00029 |
| East Asian8 / 44,806 | 0.00018 |
| Remaining individuals9 / 62,452 | 0.00014 |
| European (Finnish)9 / 63,964 | 0.00014 |
| South Asian12 / 91,022 | 0.00013 |
| Ashkenazi Jewish3 / 29,586 | 0.0001 |
| Admixed American5 / 59,940 | 8.3e-05 |
| European (non-Finnish)89 / 1,179,316 | 7.5e-05 |
| Ashkenazi Jewish25 / 10,202 | 0.0025 |
| European (Finnish)46 / 25,042 | 0.0018 |
| European (non-Finnish)164 / 128,320 | 0.0013 |
| Remaining individuals9 / 7,192 | 0.0013 |
| East Asian24 / 19,946 | 0.0012 |
| Admixed American38 / 35,228 | 0.0011 |
| African/African American18 / 24,934 | 0.00072 |
| South Asian21 / 30,522 | 0.00069 |
This variant is present in gnomAD v4.1 (AF= 9.85752e-05; MAF= 0.00986%, 159/1612982 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.00033036; MAF= 0.03304%, 2/6054 alleles, homozygotes = 0); grpmax FAF= 0.00019859.
This variant is present in gnomAD v2.1 (AF= 0.00122607; MAF= 0.12261%, 345/281386 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.0024505; MAF= 0.24505%, 25/10202 alleles, homozygotes = 0); grpmax FAF= 0.00119554.
Not available in gnomAD-Canada v1.0.
The variant is a missense substitution, NM_000157.4:c.1448T>C (p.Leu483Pro), so the applicable generic PP3/BP4 path is REVEL only; SpliceAI is not used for a missense variant, and BayesDel has no generic ACMG-strength calibration. REVEL is 0.858, meeting the supplied PP3 moderate threshold of >=0.773 but not the strong threshold of >=0.932. Therefore PP3 is met at moderate strength, based on the ClinGen SVI REVEL calibration of Pejaver et al. 2022 (PMID:36413997).
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
The variant is a missense substitution, so REVEL is the sole applicable generic BP4 path; SpliceAI is not used for a missense variant, and BayesDel has no generic ACMG-strength calibration. REVEL is 0.858, which is above the supplied BP4 supporting threshold of <=0.29 and therefore is not evidence for a benign computational effect. The result is not_met rather than not_applicable: missense variants are within BP4 scope, but this applicable REVEL result does not meet BP4.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_000157.4:c.1448T>C in GBA1 is a missense substitution predicted to produce NP_000148.2:p.(Leu483Pro). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for GBA1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.858. BayesDel score = 0.55942.
8 paper records listed. 4 cited in the classification.
Homozygosity for the singly mutated 6433C allele (Leu-444 — Pro-444) is found in type 3 disease, as well as in children with severe visceral involvement (Tsuji et al, 1987; Latham et al, 1990) and is the major mutation in the Norbottnian form of type 3 disease (Latham et al, 1990).
Location Introduction, p. 16; Results/Table 1, pp. 17-19
Context Mutation and polymorphism spectrum analysis in Gaucher disease patients with genotype and phenotype comparisons.
We found the point mutation Leu-444 (CTG) to Pro (CCG) in one type 2 (GM-0877) patient.
Location Results, identified mutations; Discussion, mutant protein expression and degradation
Context Molecular analysis of Gaucher disease cell lines followed by mutant cDNA expression studies in NIH-3T3 cells.
p.L444P was the most frequent mutation seen in FPD patients (12 of 144 = 8.3%, Table 3).
Location Results, sections 3.1–3.2; Table 3; Family 28 in Fig. 2
Context Japanese cohort of 147 familial Parkinson disease patients from 144 families and 100 unrelated controls; direct sequencing of GBA coding exons and exon-intron boundaries with family testing.
Mutational analysis showed that the family carried a known complex allele which included mutations at amino acids L444P, A456P, and V460V.
Location Abstract; Results, Mutation analysis; Enzyme activity; Western analysis
Context Family report of lethal perinatal type 2 Gaucher disease with mutation analysis, enzyme activity testing, and western analysis.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 9.85752e-05; MAF= 0.00986%, 159/1612982 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.00033036; MAF= 0.03304%, 2/6054 alleles, homozygotes = 0); grpmax FAF= 0.00019859.
This variant is present in gnomAD v2.1 (AF= 0.00122607; MAF= 0.12261%, 345/281386 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.0024505; MAF= 0.24505%, 25/10202 alleles, homozygotes = 0); grpmax FAF= 0.00119554.
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Pathogenic (41 clinical laboratories) and as risk factor (1 clinical laboratory) and as pathogenic (1 clinical laboratory) and as Likely pathogenic (1 clinical laboratory) and as Likely Pathogenic (1 clinical laboratory). (ClinVarID = 4288)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.858. BayesDel score = 0.55942.
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.